Over the last decades there has been a growing understanding of the biological effects of vitamin D. The classical actions of vitamin D involve calcium and phosphate absorption from the intestines, which is vital to the mineral balance and to the build-up and maintenance of bones. Another primary action of vitamin D is the regulation of the excretion of the parathyroid hormone (PTH) from the parathyroid glands. Vitamin D inhibits the production of the parathyroid hormone, so that a low level of vitamin D in the blood will lead to a high level parathyroid hormone, and vice versa. Vitamin D exerts its effect through an intriguing mechanism whereby the production of the mRNA which is translated into the parathyroid hormone, or a proform thereof, is inhibited. The impact of vitamin D in biological systems, however, reaches beyond these effects. Vitamin D appears to have profound effects on muscles, the immune system, the reproductive system, and cell proliferation and differentiation. Cells holding the vitamin D receptor (VDR) have, in fact, been found in many parts of the body, including the intestines, kidneys, prostate, bone, bone marrow, parathyroid glands, skin, liver, muscle and lymphoid tissue. The widespread existence of VDR have made vitamin D and analogues thereof attractive compounds for the treatment of various diseases including cancer, skin and bone diseases and autoimmune diseases.
The invention relates to a novel class of vitamin D analogues that show a potent suppressive effect on the secretion of parathyroid hormone, i.e. which can be used in the treatment of secondary hyperparathyroidism (s-HPT). A crucial structural element in active vitamin D are the two hydroxyl groups in positions 1 and 25. In contrast to that, the compounds of the present invention are characterized by a blocking of the 25-position, so that they do not have hydroxyl groups in that position, nor can they be hydroxylated in that position in vivo by a P450-like enzyme.
Vitamin D analogues with some structural resemblance to the compounds of the present invention have previously been disclosed. As an example, WO95/02577 teaches compounds of the formula
WO91/00855 discloses compounds of the formula
and Onisko, Tetrahedron Lett., 1107-1108, 13, 1977 discloses a compound of the formula
which is useful for inhibition of liver enzymes responsible for hydroxylation of vitamin D3 to 25-OH vitamin D3.
Finally, Bogoslovsky et al, Vitamin D—Basic Research and its Clinical Application, proceedings of the Fourth Workshop on Vitamin D, Berlin West Germany 1979, A. W. Norman et al (Eds.), p 1257-1259, Walter de Gruyter, Berlin 1979, discloses a synthetic study including the preparation of 3(S)-hydroxy-9,10-secocholesta-5(Z),7(E),10(19),22(E),24-penta-ene. This reference, however, does not disclose any biological data on this particular compound.
Vitamin D and analogues thereof are already used in the treatment of s-HPT. Paricalcitol (19-nor-1,25-dihydroxy-vitamin D2) and doxercalciferol (1α-hydroxy-vitamin D2) are approved in the USA for treatment of s-HPT, and 22-oxa-calcitriol (maxacalcitol) and hexafluoro-calcitriol (falecalcitriol) are approved in Japan [Malluche, Kidney Int., 367-374, 62, 2002]. Moreover, calcitriol itself and a prodrug thereof 1α(OH)D3 are also used in the treatment and prophylaxis of s-HPT [Brandi, Nephrol Dial Transplant, 829-842, 17, 2002].
All therapeutic interventions which include administration of vitamin D and analogues thereof must pay attention to the adverse side effects often associated with this kind of therapy, in particular the calcemic effects of vitamin D compounds. These side effects may severely restrict or even prevent the use of such compounds, in spite of other clinically positive effects. The present invention therefore seeks to provide vitamin D analogues which have a reduced calcemic effect while retaining a suppressive effect on the secretion of the parathyroid hormone.